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      Mast Cell Function : A New Vision of an Old Cell

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          Abstract

          Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role.

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          STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx.

          Ca(2+) signaling in nonexcitable cells is typically initiated by receptor-triggered production of inositol-1,4,5-trisphosphate and the release of Ca(2+) from intracellular stores. An elusive signaling process senses the Ca(2+) store depletion and triggers the opening of plasma membrane Ca(2+) channels. The resulting sustained Ca(2+) signals are required for many physiological responses, such as T cell activation and differentiation. Here, we monitored receptor-triggered Ca(2+) signals in cells transfected with siRNAs against 2,304 human signaling proteins, and we identified two proteins required for Ca(2+)-store-depletion-mediated Ca(2+) influx, STIM1 and STIM2. These proteins have a single transmembrane region with a putative Ca(2+) binding domain in the lumen of the endoplasmic reticulum. Ca(2+) store depletion led to a rapid translocation of STIM1 into puncta that accumulated near the plasma membrane. Introducing a point mutation in the STIM1 Ca(2+) binding domain resulted in prelocalization of the protein in puncta, and this mutant failed to respond to store depletion. Our study suggests that STIM proteins function as Ca(2+) store sensors in the signaling pathway connecting Ca(2+) store depletion to Ca(2+) influx.
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            IgG Fc receptors.

            Since the description of the first mouse knockout for an IgG Fc receptor seven years ago, considerable progress has been made in defining the in vivo functions of these receptors in diverse biological systems. The role of activating Fc gamma Rs in providing a critical link between ligands and effector cells in type II and type III inflammation is now well established and has led to a fundamental revision of the significance of these receptors in initiating cellular responses in host defense, in determining the efficacy of therapeutic antibodies, and in pathological autoimmune conditions. Considerable progress has been made in the last two years on the in vivo regulation of these responses, through the appreciation of the importance of balancing activation responses with inhibitory signaling. The inhibitory FcR functions in the maintenance of peripheral tolerance, in regulating the threshold of activation responses, and ultimately in terminating IgG mediated effector stimulation. The consequences of deleting the inhibitory arm of this system are thus manifested in both the afferent and efferent immune responses. The hyperresponsive state that results leads to greatly magnified effector responses by cytotoxic antibodies and immune complexes and can culminate in autoimmunity and autoimmune disease when modified by environmental or genetic factors. Fc gamma Rs offer a paradigm for the biological significance of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.
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              Th17: an effector CD4 T cell lineage with regulatory T cell ties.

              The naive CD4 T cell is a multipotential precursor with defined antigen recognition specificity but substantial plasticity for development down distinct effector or regulatory lineages, contingent upon signals from cells of the innate immune system. The range of identified effector CD4 T cell lineages has recently expanded with description of an IL-17-producing subset, called Th17, which develops via cytokine signals distinct from, and antagonized by, products of the Th1 and Th2 lineages. Remarkably, Th17 development depends on the pleiotropic cytokine TGF-beta, which is also linked to regulatory T cell development and function, providing a unique mechanism for matching CD4 T cell effector and regulatory lineage specification. Here, we review Th17 lineage development, emphasizing similarities and differences with established effector and regulatory T cell developmental programs that have important implications for immune regulation, immune pathogenesis, and host defense.
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                Author and article information

                Journal
                J Histochem Cytochem
                J. Histochem. Cytochem
                JHC
                spjhc
                Journal of Histochemistry and Cytochemistry
                SAGE Publications (Sage CA: Los Angeles, CA )
                0022-1554
                1551-5044
                October 2014
                October 2014
                : 62
                : 10 , Collagen Fiber Networks in Normal and Pathologic Tissues
                : 698-738
                Affiliations
                [1-0022155414545334]Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil (EZMDS, MCJ, CO)
                Author notes
                [*]Constance Oliver, PhD, Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto 14049-900, SP, Brazil. E-mail: coliver@ 123456fmrp.usp.br
                Article
                10.1369_0022155414545334
                10.1369/0022155414545334
                4230976
                25062998
                d5b58923-21c4-4168-b643-4e55609df930
                © The Author(s) 2014

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page( http://www.uk.sagepub.com/aboutus/openaccess.htm).

                History
                : 18 March 2014
                : 7 July 2014
                Categories
                Review

                mast cells,origin,function,mdiators,activation,immunity
                mast cells, origin, function, mdiators, activation, immunity

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